Cardiac repolarization alternans is defined as a beat-to-beat alternation in electrocardiogram T-wave morphology corresponding to alternating changes in action potential duration. Because of the putative link between repolarization alternans and the onset of ventricular fibrillation, it may be clinically beneficial to prevent and terminate alternans. Alternans control by way of pharmacological agents that alter individual ion channel kinetics has yet to prove clinically feasible. Closed-loop feedback systems aimed at controlling alternans via one control site are effective only locally, with efficacy decaying as a function of distance from the stimulating electrode. However, this has been explicitly shown only for Purkinje fibers;alternans control data does not exist for the more clinically relevant ventricular tissue. Specific Aim 1 of this proposal is to characterize alternans control in ventricular tissue. Alternans information from ventricular tissue is needed before additional steps in alternans therapy can be taken. Specifically, the objectives of this aim are: 1) Using the Shiferaw-Sato-Karma (SSK) canine ventricular ionic model, elucidate single-site spatiotemporal alternans control in simulated single cell, 1-D (fiber) and 2-D (sheet). 2) Characterize single-site spatiotemporal alternans control in arterially perfused right ventricular canine tissue preparations using a real-time optical mapping system. Previous computational, experimental and theoretical research on alternans control suggests that single-site spatiotemporal control fails at points distal to the stimulation electrode. Specific Aim 2 of this proposal is to develop a multisite control system based on the quantified dynamics from Aim 1 in order to control alternans in larger pieces of cardiac tissue. Specifically, the objectives of this aim are: 1) Simulate multisite alternans control using the SSK model in 1-D (fiber) and 2-D (sheet) by modifying the standard delayed feedback alternans control algorithm such that evenly spaced control sites cooperatively control alternans along the length of realistically long fibers and 2-D sheets of tissue. 2) Apply the developed multisite alternans control method in right ventricular canine tissue preparations using multiple bipolar electrodes. Lay summary: Cardiac alternans, a rhythm disturbance in the heart that corresponds to alternations in cardiac cell behavior, has been closely linked to the onset of debilitating heart arrhythmias as well as sudden cardiac death. This research will help investigators better understand this cardiac disturbance as well as provide clinically viable techniques capable of preventing/terminating this potentially dangerous occurrence.